Imidazoline receptors were first proposed based on the observation that the vasodepressor action of centrally administered clonidine could not be mimicked or blocked by adrenergic compounds lacking an imidazoline structure P. Bousquet, et al., Eur. J. Pharmacol. 34:151-156 (1975)!. Later, radioligand binding studies in bovine ventrolateral medulla using labelled clonidine and idazoxan demonstrated two populations of nonadrenergic binding sites, now referred to as imidazoline binding sites I.sub.1 (labeled by clonidine) and I.sub.2 (labeled by idazoxan) P. Ernsberger, et al., Eur. J. Pharmacol. 134:1-13 (1987)!.
I.sub.1 -sites are localized to plasma membranes, enriched in ventrolateral medullary neurons, kidney medulla and platelets and appear functionally coupled to central sympathetic outflow. I.sub.2 -sites also are widely distributed throughout the mammalian brain and periphery (liver, kidney cortex, fat cells, platelets, placenta, vascular smooth muscle and endothelium) S. Regunathan, et al, J. Pharmacol. Exp. Ther. 276:1272-1282 (1996); M. C. Michel, et al, TIPS 10:342-344 (1989) and S. Regunathan, et al, Ann. Rev. Pharmacol. Toxicol. 36:511-544 (1996)!, but their functional role is uncertain. D. J. Nutt, et al, The imidazoline receptor: pharmacology, functions, ligands, and relevance to biology and medicine, D. J. Reis, P Bousquet and A. Parini (Eds.) 125-139, The New York Acadamy of Sciences, New York (1995)!.
Monoamine oxidase (MAO) activity is closely coupled with I.sub.2 binding F. Tesson, et al., Eur. J. Pharmacol. 208:81-83 (1991)!. Both .sup.3 H!idazoxan binding and enzymatic activity are co-localized to the mitochondrial outer membrane F. Tesson, et al., J. Biol. Chem., 279:9856-9861 (1995)!. Partially purified I.sub.2 binding protein has been shown to possess amino acid sequences in common with MAO-A and MAO-B. Yeast cells transformed with recombinant cDNA encoding human MAO-A or MAO-B, express a protein that specifically binds .sup.3 H!idazoxan F. Tesson, et al., J. Biol. Chem. 270:9856-9861 (1995)!. It appears, however, that the substrate (or active) binding site of the enzyme is distinct from the I.sub.2 ligand recognition site I. Limon-Boulez, et al., J. Pharmacol. Exp. Ther. 276:359-364 (1996); C. Carpene et al, J. Pharmacol. Exp. Ther. 272:681-688 (1995); and R. Raddatz, et al., J. Biol. Chem. 270:27961-27968 (1995)!.
Also, a disparity in MAO activity and imidazoline binding has been seen using the irreversible I.sub.2 binding ligand (.sup.125 I)AZIPI such that photolabeling could be demonstrated in liver membranes but not in platelets despite equivalent amount of MAO B activity. R. Raddatz, et al, J. Biol. Chem., 270:27961-8 (1995)!.
MAO activity is widely distributed, but the expression of I.sub.2 sites appears to be tissue specific F. Tesson, et al., Eur. J. Pharmacol. 219:335-338 (1992)!. Thus, it remains conjectural whether 12 sites and MAO are the same protein in all tissues S. Regunathan, et al, Ann. Rev. Pharmacol. Toxicol. 36:511-544 (1996)!.
Binding to I.sub.2 -sites was initially described using the non-selective .alpha..sub.2 antagonist .sup.3 H!idazoxan in the presence of an .alpha..sub.2 -receptor mask M. C. Michel, et al, TIPS 10:342-344 (1989)!. Recently, highly selective I.sub.2 -ligands have been described such as 2-(3-azido or amino-4-iodophenoxyl)methyl imidazoline S. M. Lanier, et al., J. Biochem. Mol. Biol. 268:16047-16051 (1993)); B. Ivkovic, et al., Mol. Pharmacol. 46:15-23 (1994)), and 2-(2-benzofuranyl)-2-imidazoline (BFI) D. J. Nutt, et al., The imidazoline receptor: pharmacology, functions, ligands, and relevance to biology and medicine, D. J. Reis, et al., (Eds.) 125-139, The New York Academy of Sciences, New York (1995) (Eds.)!. Unlabelled BFI is over 20 times more selective for .sup.3 H!idazoxan sites in rat liver (I.sub.2) compared to .sup.3 H!RX821002 sites in hamster adipocytes) C. Carpene, et al., J. Pharmacol. Exp. Ther. 272:681-688 (1995)!. Further, in rabbit whole brain membranes, .sup.3 H!BFI binds with high affinity to an apparent single population of sites and has nearly 3 orders of magnitude greater selectivity for I.sub.2 sites than for .alpha..sub.2 sites D. J. Nutt, et al., The imidazoline receptor: pharmacology, functions, ligands, and relevance to biology and medicine, D. J. Reis Bousquet, P. and Parini, A., 125-139, The New York Academy of Sciences, New York (1995)!. As yet, there is no information available on the relationship between .sup.3 H!BFI binding and MAO activity in human tissues.
Tranylcypromine (TCP) is a non-selective cyclopropylamine MAO inhibitor, that acts as a highly effective antidepressant agent although its use is restricted because of potential side effects associated with its inhibitory action on MAO.
There exists a need to develop compounds which mimic the effects of TCP without the adverse side effects associated with TCP.